Esters of thienyl carboxylic acids and amino alcohols and their quaternization products

ABSTRACT

Compounds of the formula 
                 
 
of which, in exemplary compounds, the thienyl group is attached via the 2-position and;
         (a) A is 3α-(6β, 7β-epoxy)-tropanyl methobromide and R 1  is 2-thienyl;   (b) A is 3α-(6, 7dehydro)-tropanyl methobromide and R 1  is 2-thienyl;   (c) A is 3β-tropanyl methobromide and R 1  is 2-thienyl; and,   (d) A is 3α-(N-isopropyl)-nortropanyl methobromide and R 1  is cyclopentyl.
 
There are anticholinergics. Administered by inhalation, they are useful for the treatment of chronic obstructive bronchitis or slight to moderately severe asthma. Administered by the intravenous or oral routes, they are useful for the treatment of vagally induced sinus bradycardia.

This is a continuation of application Ser. No. 08/254,324, filed on Jun.6, 1994, now abandoned which is a continuation of application Ser. No.08/100,822, filed on Aug. 2, 1993, now abandoned, which is acontinuation of application Ser. No. 07/838,724, filed on Mar. 13, 1992,now abandoned.

The invention relates to novel thienylcarboxylates of amino alcohols andtheir quaternary products and to the preparation of the novel compoundsand their use as active ingredients in medicaments.

The novel compounds correspond to the formula

in which

-   -   A represents the group        wherein    -   m and n independently of one another denote 1 or 2,    -   Q represents one of the double-bonding groups        and    -   Q′ represents the group ═NR or the group ═NRR′, wherein    -   R denotes H or an optionally halogen-substituted or        hydroxy-substituted C₁-C₄-alkyl radical, R′ denotes a        C₁-C₄-alkyl radical and R and R′ together may also form a        C₄-C₆-alkylene radical, and wherein, in the case of quaternary        compounds, one equivalent of an anion (X⁻)opposes the positive        charge of the N atom,    -   R₁ represents a thienyl, phenyl, furyl, cyclopentyl or        cyclohexyl radical, wherein these radicals may also be        methyl-substituted, thienyl and phenyl may also be        fluoro-substituted or chloro-substituted,    -   R₂ represents hydrogen, OH, C₁-C₄-alkoxy or C₁-C₄-alkyl,    -   R_(a) represents H, F, Cl or CH₃ and, if ═NR denotes a secondary        or tertiary amino group, also the acid addition salts.

In the compounds of formula I, R₁ preferably represents thienyl, R₂preferably represents OH. The group —OA preferably has theα-configuration and is derived from, for example scopine, tropine,granatoline or 6,7-dehydrotropine or the corresponding nor-compounds;however, —OA may also have the β-configuration, as in pseudotropine,pseudoscopine.

Corresponding radicals are, for example

The substituent R is preferably a lower alkyl radical, such as CH₃,C₂H₅, n-C₃H₇, i-C₃H₇, R′ is preferably CH₃. R and R′ together are, forexample —(CH₂)₅—. As halogen substituents for R, F or, as second choice,Cl are suitable.

If R denotes a halogen-substituted or hydroxy-substituted alkyl radical,it is preferably —CH₂—CH₂F or —CH₂—CH₂OH. Accordingly, the group Arepresents, for example the radicals of scopine, N-ethylnorscopine,N-isopropylnorscopine, tropine, N-isopropylnortropine,6,7-dehydrotropine, N-β-fluoroethylnortropine,N-isopropyl-6,7-dehydronortropine, N-methylgranatoline or thecorresponding quaternary compounds, wherein the anion is preferably Br⁻or CH₃SO₃ ⁻.

As the acid radical

the following are particularly suitable:

The quaternary compounds are particularly suitable for therapeuticapplication, whereas the tertiary compounds are important not only asactive ingredients but also as intermediate products.

The compounds of the invention are strong anti-cholinergic agents andhave prolonged action. Action lasting at least 24 hours is achieved atinhaled dosages in the μg range. In addition, the toxicity is in thesame range as the commercial product Ipratropium bromide, while at thesame time the therapeutic effect is stronger.

The novel compounds are suitable, in accordance with theiranti-cholinergic nature, for example for the treatment of chronicobstructive bronchitis and (slight to moderately severe) asthma, alsofor the treatment of vagally induced sinus bradycardia.

Whereas application of the novel active ingredients (in particular thequaternary compounds) by inhalation is mainly recommended forrespiratory tract diseases, as a result of which side-effects arelargely eliminated, the application for sinus bradycardia is preferablycarried out intravenously or orally. It has thus proved to beadvantageous that the novel compounds leave the gastro/intestinalmotility largely unaffected.

For administration the compounds of the invention are processed usingknown auxiliaries and/or excipients to give conventional galenicpreparations, for example inhalation solutions, suspensions in liquifiedpropellants, preparations containing liposomes or proliposomes,injection solutions, tablets, coated tablets, capsules, inhalationpowders for use in conventional inhalation apparatus.

Formulation examples (measures in weight per cent):

1. Controlled dosage aerosol Active ingredient according to theinvention 0.005 Sorbitan trioleate 0.1 monofluorotrichloromethane and to100 Difluorodichloromethane 2:3

The suspension is poured into a conventional aerosol container with adosage valve. 50 μl of suspension are preferably dispensed peractuation. The active ingredient may also be metered in a higher amountif required (for example 0.02 wt. %).

2. Tablets Active ingredient according to the invention 0.05 Colloidalsilicic acid 0.95 Lactose 65.00 Potato starch 28.00 Polyvinylpyrrolidone3.00 Na cellulose glycolate 2.00 Magnesium stearate 1.00The constituents are processed in conventional manner to give tablets of200 mg.

The advantageous properties of the novel compounds are shown, forexample, in the inhibition of broncholysis in the rabbit (acetylcholinespasms intravenously). After intravenous administration of the novelactive ingredients (dosage 3 μg/kg intravenously), the maximum effectoccurred after 10 to 40 minutes. After 5 hours the inhibiting effect hadstill not been reduced to half, that is to say the half effect time ismore, in some cases considerably more, than 5 hours, as made clear bythe residual effects after 5 hours listed below:

Compound Residual effect in % A 76 B 76 C 81 D 61 E 68 F 73 G 69Compounds of the formula

Com- pound A R₁ A

2- thienyl B

3- thienyl D

2- thienyl E

3- thienyl F

cyclo- pentyl G

cyclo- pentyl Compound C

Notes: 1. The compounds in which R₁ is not 2-thienyl are racemates. 2.The compounds are 3α-compounds in each case.Processes known per se are used to prepare the novel compounds.

An ester of the formula

wherein R″ represents a C₁-C₄-alkyl radical, preferably a methyl orethyl radical (R₁, R₂ and R_(a) have the above meanings), is preferablytransesterified using an amino alcohol of the formula

wherein m, n and Q have the above meanings, Q″ represents ═NR or ═NH andthe OH group is in the α- or β-position, in the presence of aconventional transesterification catalyst, and the compound obtained isoptionally quaternised

-   -   a) if Q″ denotes ═NR (R≢H), using a reactive monofunctionalised        derivative Z-(C₁-C₄-alkyl) of a corresponding alkane (Z=leaving        group)        or is optionally quaternised    -   b) if Q″ denotes ═NH, using a terminally disubstituted alkane        Z-(C₄-C₆-alkylene)-Z without isolation of intermediates.

The transesterification is carried out with heat in an organic solvent,for example toluene, xylene, heptane, or in a melt, strong bases such assodium methylate, sodium ethylate, sodium hydride, metallic sodium,being used as catalyst. Reduced pressure is used to remove the releasedlower alcohol from the equilibrium, the alcohol is optionally distilledoff azeotropically. The transesterification takes place at temperatureswhich in general do not exceed 95° C. Transesterification often proceedsmore favourably in a melt. If required, the free bases may be obtainedin a manner known per se from acid addition salts of the tertiary aminesusing suitable basic compounds. Quaternisation is carried out insuitable solvents, for example acetonitrile or acetonitrile/methylenechloride, preferably at room temperature; a corresponding alkyl halide,for example alkyl bromide, is preferably used in the process asquaternising agent. Transesterification products wherein Q′ representsNH are used as starting materials for those compounds in which R and R′together represent a C₄-C₆-alkylene group. Conversion into the tertiaryand then quaternary compound then takes place with the aid of suitable1,4-dihaloalkanes, 1,5-dihaloalkanes or 1,6-dihaloalkanes withoutisolation of intermediates.

The starting materials may be obtained analogously to known compounds—inas much as they have not already been described.

EXAMPLES

-   methyl di-(2-thienyl)glycolate from dimethyl oxalate and 2-thienyl    magnesium bromide;-   ethyl di-(2-thienyl)glycolate from (2-thienyl)glyoxylic acid and    2-thienyl lithium;-   ethyl hydroxy-phenyl-(2-thienyl)acetate from methyl phenylglyoxylate    and 2-thienyl magnesium bromide or from methyl (2-thienyl)glyoxylate    and phenyl magnesium bromide.-   Methyl 2-thienylglyoxylate and cyclohexyl or cyclopentyl magnesium    bromide may be reacted in a similar manner.

Several processes are also available for the preparation of the aminoalcohols.

Pseudoscopine may be obtained in accordance with M. Polonovski et al.,Bull. soc. chim. 43, 79 (1928). Pseudotropenol may be removed from themixture, (fractional crystallisation or distillation) which is obtained,for example in accordance with V. Hayakawa et al., J. Amer. Chem. Soc.1978, 100(6), 1786 or R. Noyori et al., J. Amer. Chem. Soc. 1974,96(10), 3336.

The corresponding methyl esters may be prepared in a conventional mannerstarting from 2-furylglyoxylnitrile or 3-furylglyoxylnitrile via the2-furylglyoxylic acid or 3-furylglyoxylic acid which can be obtainedtherefrom. The corresponding glycolates are obtained from these asdescribed using the organometallic derivatives of 2-bromothiophene or3-bromothiophene. The organometallic compounds which can be obtainedfrom 2-, 3- or 4-halopyridine can be reacted with methyl2-thienylglyoxylate or methyl 3-thienylglyoxylate to give thecorresponding glycolates.

Thienylglycolates, in which the thiophene ring contains fluorine in the2- or 3-position, are prepared, for example starting from2-fluorothiophene or 3-fluorothiophene (bromination to give2-bromo-3-fluorothiophene or 2-bromo-5-fluorothiophene), and afterconversion to the corresponding organometallic compounds, reaction withsuitable glyoxylates to give the glycolates.

2-Fluorothiophene and 3-fluorothiophene can be reacted analogously togive the corresponding glyoxylates Unterhalt, Arch. Pharm. 322, 839(1989) which in turn, as already described, may be reacted with, forexample 2-thienyl or 3-thienyl derivatives, to give glycolates.Symmetrically substituted di-thienylglycolates can be preparedanalogously by selecting suitable components.

A further route is available via a process analogous to the benzoincondensation and benzilic acid rearrangement.

The following examples illustrate the invention without limiting it.

EXAMPLE 1 EXAMPLE 1 Scopine di-(2-thienyl)glycolate

50.87 g (0.2 mole) of methyl di-(2-thienyl)glycolate and 31.04 g (0.2mole) of scopine are dissolved in 100 ml of absolute toluene and reactedat a bath temperature of 90° C. with addition of 1.65 g (0.071 gramatom) of sodium in several portions. The resulting methanol is distilledoff at a reaction mixture temperature of 78°-90° C. under a pressure of500 mbar. After a reaction time of about 5 hours, the reaction mixtureis stirred into a mixture of ice and hydrochloric acid. The acid phaseis separated off, rendered alkaline using sodium carbonate and the freebase is extracted using methylene chloride. After drying over sodiumsulphate, the methylene chloride is distilled off under reduced pressureand the residue is recrystallised from acetonitrile; beige-colouredcrystals (from acetonitrile).

m.p. 149°-50° C.

Yield: 33.79 g (44.7% of theoretical).

EXAMPLE 2 Scopine di-(2-thienyl)glycolate

12.72 g (0.05 mole) of methyl di-(2-thienyl)glycolate and 7.76 g (0.05mole) of scopine are melted in a heating bath at 70° C. under a waterjet vacuum. 2.70 g (0.05 mole) of sodium methylate are introduced intothis melt and heated for 1 hour in a heating bath at 70° C. under awater jet vacuum and subsequently for a further hour in a heating bathat 90° C. The solidified melt is taken up in a mixture of 100 ml ofwater and 100 ml of methylene chloride while monitoring the temperature,and the methylene chloride phase is extracted several times using water.The methylene chloride phase is extracted using the corresponding amountof dilute hydrochloric acid. The scopine di-(2-thienyl)glycolate isextracted from the combined aqueous phases using methylene chlorideafter adding the corresponding amount of sodium carbonate and dried oversodium sulphate. The hydrochloride is prepared from the dried methylenechloride solution in a conventional manner. The crystals are filteredoff under suction, washed using acetone and dried under reduced pressureat 35° C. Pale yellow crystals (from methanol), m.p. 238°-41° C.(decomposition);

Yield: 10.99 g (53.1% of theoretical).

The hydrochloride may be converted to the base in a conventional manner.

EXAMPLE 3 Scopine di-(2-thienyl)glycolate

38.15 g (0.15 mole) of methyl di-(2-thienyl)glycolate and 23.28 g (0.15mole) of scopine are mixed, 0.34 g (0.015 gram atom) of sodium is addedand the mixture is melted in a heating bath at 90° C. under a water jetvacuum. The reaction lasts 2.5 hours. 100 ml of absolute toluene arethen added and the mixture is stirred at a heating bath temperature of90° C. until a solution is produced. The reaction solution is cooled toroom temperature and stirred into a mixture of ice and hydrochloric acidcooled using ice. The hydrochloride of the basic ester crystallising outis filtered off under suction and washed using a small amount of waterand a large amount of diethyl ether. The filtrate phases are separatedoff and the aqueous phase is extracted using diethyl ether. Thehydrochloride filtered off under suction is suspended in the (acid)aqueous phase and converted to the base while monitoring the temperatureand adding the corresponding amount of sodium carbonate; the base isextracted using methylene chloride. The combined methylene chloridephases are dried over sodium sulphate. After distilling off themethylene chloride, crystals remain which are purified over activecharcoal and recrystallised from acetonitrile. Pale yellow crystals(from acetonitrile), m.p. 148°-49° C.;

Yield: 39.71 g (70.1% of theoretical).

TABLE I Compounds of the formula

M.p. [° C.] Hydro- No. A R₁ Base chloride 1 3α-(6β,7β-epoxy)-tropanyl2-thienyl 149-50 238-41 2 3α-tropanyl 2-thienyl 167-8  253 33α-(6,7-dehydro)-tropanyl 2-thienyl 164-5  4 3α-(N-β-fluoroethyl)-2-thienyl 236 nortropanyl 5 3α-(N-isopropyl)- 2-thienyl 232 granatanyl 63α-(N-isopropyl)- 2-thienyl 256 nortropanyl 7 3α-(6β,7β-epoxy)-N-2-thienyl 206 isopropyl-nortropanyl 8 3α-(6β,7β-epoxy)-N-ethyl 2-thienyl212-3 nortropanyl 9 3α-(N-ethyl)-nortropanyl 2-thienyl 256-7 103α-(N-N-methyl)- 2-thienyl 241 granatanyl 11 3α-(6β,7β-epoxy)-N-β2-thienyl 188-90 fluoroethylnortropanyl 12 3α-(6β,7β-epoxy)-N-n2-thienyl 104-6 propylnortropanyl 13 3α-(6β,7β-epoxy)-N-n 2-thienyl225-7 butylnortropanyl 14 3α-(6β,7β-epoxy)-tropanyl phenyl 246-7 153α-tropanyl phenyl 243-4 16 3α-(N-β-fluoroethyl)- phenyl 219-20nortropanyl 17 3α-(6,7-dehydro)-tropanyl phenyl 181-3 183α-(N-ethyl)-nortropanyl phenyl 231-2 19 3α-(N-isopropyl)- phenyl 246-7nortropanyl 20 3α-tropanyl cyclo- 260 hexyl 21 3α-(N-β-fluoroethyl)-cyclo- 203-4 nortropanyl hexyl 22 3α-(6β,7β-epoxy)-tropanyl cyclo- 237pentyl 23 3α-tropanyl cyclo- 260 pentyl 24 3α-(N-β-fluoroethyl)- cyclo-182-3 nortropanyl pentyl 25 3α-(N-ethyl)-nortropanyl cyclo- 227-8 pentyl26 3α-(N-isopropyl)- cyclo- 174-5 nortropanyl pentyl 273α-(6β,7β-epoxy)-tropanyl 2-thienyl 240-2 28 3β-tropanyl 2-thienyl 217-929 3β-(6,7-dehydro)-tropanyl 2-thienyl 233-5 303α-(6,7-dehydro)-trapanyl 3-thienyl 247-8 31 3α-(6β,7β-epoxy)-tropanyl3-thienyl 242-3 32 3α-(6β,7β-epoxy)-tropanyl 2-furyl 333α-(6,7-dehydro)-tropanyl 2-furyl 34 3α-tropanyl 2-furyl 35 3α-tropanyl2-pyridyl 36 3α-(6β,7β-epoxy)-tropanyl 2-pyridyl 373α-(6,7-dehydro)-tropanyl 2-pyridyl 38 3α-tropanyl 3-thienyl 393α-(6,7-dehydro)-tropanyl cyclo- pentyl 40 3α-(6β,7β-epoxy)-tropanylcyclo- hexyl 41 3α-(6,7-dehydro)-tropanyl cyclo- hexyl Note: Allhydrochlorides melt with decomposition.

EXAMPLE 4 Scopine di-(2-thienyl)glycolate methobromide

10.0 g (0.0265 mole) of scopine di-(2-thienyl)glycolate are dissolved ina mixture comprising 20 ml of anhydrous methylene chloride and 30 ml ofanhydrous acetonitrile and treated with 12.8 g (0.1325 mole) of methylbromide (as 50% strength solution in anhydrous acetonitrile), and thereaction mixture is allowed to stand for 24 hours at room temperature ina tightly sealed reaction vessel. Crystals are precipitated during thistime. They are filtered off under suction, washed using methylenechloride and dried at 35° C. under reduced pressure. White crystals(from methanol/acetone), m.p. 217°-8° C. (decomposition) after drying at111° C. under reduced pressure.

TABLE II Quaternary compounds of the formula

No. A R₁ M.p. [° C.] 1 3α-(6β,7β-epoxy)-tropanyl 2-thienyl 217-18methobromide 2 3α-tropanyl methobromide 2-thienyl 263-64 33α-(6,7-dehydro)-tropanyl 2-thienyl 191-92 methobromide 43α-(N-β-fluoroethyl)- 2-thienyl 242-43 nortropanylmethobromide 53α-tropanyl-β- 2-thienyl 214-15 fluoroethobromide 6 3α-(N-isopropyl)-2-thienyl 229-30 granatanyl methobromide 7 3α-(N-isopropyl)- 2-thienyl245-46 nortropanylmethobromide 8 3α-(6β,7β-epoxy)-N- 2-thienyl 223-24isopropyl-nortropanyl methobromide 9 3α-(6β,7β-epoxy)-N- 2-thienyl215-16 ethylnortropanyl methobromide 10 3α-(N-ethyl)-nortropanyl2-thienyl 260-61 methobromide 11 3α-(N-methyl)-granatanyl 2-thienyl246-47 methobromide 12 3α-(6β,7β-epoxy)-N- 2-thienyl 182-83 fluoroethyl-nortropanyl methobromide 13 3α-(6β,7β-epoxy)-N-n- 2-thienyl 209-10propylnortropanyl methobromide 14 3α-tropanyl-β- 2-thienyl 231-32hydroxyethobromide 15 3α-(6β,7β-epoxy)-tropanyl phenyl 217-18ethobromide 16 3α-tropanyl methobromide phenyl 273-74 173α-(N-β-fluoroethyl)- phenyl nortrapanylmethobromide 183α-(6,7-dehydro)-tropanyl phenyl 110-71 methobromide 193α-(N-ethyl)-nortropanyl phenyl 249-50 methobromide 20 3α-(N-isopropyl)-phenyl 259-60 nortropanyl methobromide 21 3α-tropanyl ethobromide phenyl248-49 22 3α-(N-ethyl)-nortropanyl phenyl 244-45 ethobromide 233α-(6β,7β-epoxy)-tropanyl phenyl 226 ethobromide 24 3α-tropanyl-β-phenyl 241 fluoroethobromide 25 3α-tropanyl methobromide cyclohexyl 27826 3α-(N-β-fluoroethyl)- cyclohexyl 198 nortropanyl methobromide 273α-tropanyl-β- cyclohexyl 233-34 fluoroethobromide 28 3α-tropanylmethobromide cyclopentyl 260 29 3α-tropanyl ethobromide cyclopentyl235-36 30 3α-(N-ethyl)-nortropanyl cyclopentyl 251-52 methobromide 313α-(N-isopropyl)- cyclopentyl 244-45 nortropanyl-methobromide 323α-tropanyl-β- cyclopentyl 189-90 fluoroethobromide 333α-(N-β-fluoroethyl)- cyclopentyl 226-27 nortropanyl-methobromide 343α-(6,7-dehydro)-tropanyl 2-thienyl 225-6  metho-methanesulphonate 353α-(6β,7β-epoxy)-tropanyl 2-thienyl 218-20 methobromide 36 3α-tropanylmethobromide 2-thienyl 243-4  37 3α-(6,7-dehydro)-tropanyl 2-thienyl211-4  methobromide 38 3α-(6,7-dehydro)-tropanyl 3-thienyl 182-3*methobromide 39 3α-(6β,7β-epoxy)-tropanyl 3-thienyl 217-8 methobromide40 (+) enantiomer of No. 1 41 (−) enantiomer of No. 1 423α-(6β,7β-epoxy)-tropanyl 2-furyl methobromide 433α-(6,7-dehydro)-tropanyl 2-furyl methobromide 44 3α-tropanylmethobromide 2-furyl 45 3α-(6β,7β-epoxy)-tropanyl 2-pyridyl methobromide46 3α-(6,7-dehydro)-tropanyl 2-pyridyl methobromide 47 3α-tropanylmethobromide 2-pyridyl 48 3α-tropanyl methobromide 3-thienyl 493α-(6,7-dehydro)-tropanyl cyclopentyl methobromide 503α-(6β,7β-epoxy)-tropanyl cyclohexyl methobromide 513α-(6,7-dehydro)-tropanyl cyclohexyl methobromide 523α-(6β,7β-epoxy)-tropanyl cyclohexyl methobromide *contains crystallinemethanol Note: All compounds in the table melt with decomposition.

TABLE III Compounds of the formula

M.p. [° C.] No. A R₁ Hydrochloride 1 3α-(6β,7β-epoxy)-tropanyl phenyl246-7 2 3α-(6,7-dehydro)-tropanyl phenyl 261-2 33α-(6β,7β-epoxy)-tropanyl 3-thienyl 4 3α-(6,7-dehydro)-tropanyl3-thienyl 5 3α-tropanyl 3-thienyl 6 3α-(N-methyl)-granatanyl 3-thienyl

TABLE IV Compounds of the formula

M.p. [° C.] No. A R₂ Hydrochloride 1 3α-(6β,7β-epoxy)-tropanyl H 23α-(6,7-dehydro)-tropanyl H 3 3α-(6β,7β-epoxy)-tropanyl methyl 43α-(6,7-dehydro)-tropanyl methyl 210-2.5 5 3α-(6β,7β-epoxy)-tropanylmethoxy 6 3α-(6,7-dehydro)-tropanyl methoxy

TABLE V Compounds of the formula

M.p. No. A R₂ R_(a) [° C.] 1 3α-(6β,7β-epoxy)- 2-thienyl 5-methyltropanyl 2 3α-(6,7-dehydro)- 2-thienyl 5-methyl tropanyl 3 3α-tropanyl2-thienyl 5-methyl 4 3α-(6β,7β-epoxy)- 2-(5-methyl)- 5-methyl tropanylthienyl 5 3α-(6,7-dehydro)- 2-(5-methyl)- 5-methyl tropanyl thienyl 63α-tropanyl 2-(5-methyl)- 5-methyl thienyl 7 3α-(6β,7β-epoxy)- 2-thienyl5-fluoro tropanyl 8 3α-(6,7-dehydro)- 2-thienyl 5-fluoro tropanyl 93α-tropanyl 2-thienyl 5-fluoro 10 3α-(6β,7β-epoxy)- 2-(5-fluoro)-5-fluoro tropanyl thienyl 11 3α-(6,7-dehydro)- 2-(5-fluoro)- 5-fluorotropanyl thienyl 12 3α-tropanyl 2-(5-fluoro)- 5-fluoro thienyl

TABLE VI Compounds of the formula

M.p. No. A R₁ R_(a) [° C.] 1 3α-(6β,7β-epoxy)-tropanyl 2-thienyl5-methyl methobromide 2 3α-(6,7-dehydro)-tropanyl 2-thienyl 5-methylmethobromide 3 3α-tropanyl-methobromide 2-thienyl 5-methyl 43α-(6β,7β-epoxy)-tropanyl 2-(5-methyl)- 5-methyl methobromide thienyl 53α-(6,7-dehydro)-tropanyl 2-(5-methyl)- 5-methyl methobromide thienyl 63α-tropanyl methobromide 2-(5-methyl)- 5-methyl thienyl 73α-(6β,7β-epoxy)-tropanyl 2-thienyl 5-fluoro methobromide 8a-(6,7-dehydro)-tropanyl 2-thienyl 5-fluoro methobromide 9 3α-tropanylmethobromide 2-thienyl 5-fluoro 10 3α-(6β,7β-epoxy)-tropanyl2-(5-fluoro)- 5-fluoro methobromide thienyl 11 3α-(6,7-dehydro)-tropanyl2-(5-fluoro)- 5-fluoro methobromide thienyl 12 3α-tropanyl methobromide2-(5-fluoro)- 5-fluoro thienyl

TABLE VII Compounds of the formula

No. A R₁ M.p. [° C.] 1 3α-(6β,7β-epoxy)-tropanyl phenyl 211-2 methobromide 2 3α-(6,7-dehydro)-tropanyl phenyl 158-60* methobromide 33α-(6β,7β-epoxy)-tropanyl 3-thienyl methobromide 43α-(6,7-dehydro)-tropanyl 3-thienyl methobromide 5 3α-tropanylmethobromide 3-thienyl 6 3α-(N-methyl)-granatanyl 3-thienyl methobromide*(with crystalline methanol)

TABLE VIII Quaternary compounds of the formula

No. A R₂ M.p. [° C.] 1 3α-(6β,7β-epoxy)-tropanyl H methobromide 23α-(6,7-dehydro)-tropanyl H methobromide 3 3α-(6β,7β-epoxy)-tropanylmethyl methobromide 4 3α-(6,7-dehydro)-tropanyl methyl 206-8methobromide 5 3α-tropanyl methobromide methoxy 6 3α-(N-methyl)-tropanylmethoxy methobromide

We claim:
 1. A compound of the formula

wherein Q is a group of the formula —CH₂—CH₂—, —CH═CH— or

R and R′ are each independently C₁-C₄-alkyl; R₁ is thienyl, phenyl,cyclopentyl or cyclohexyl; and, X⁻ is a physiologically acceptableanion.
 2. A compound in accordance with claim 1, of the formula

wherein R is CH₃, C₂H₅, n-C₃H₇, or i-C₃H₇; R′ is CH₃; and R₁, Q and X⁻are as defined in claim
 1. 3. A compound in accordance with claim 2wherein R₁ is thienyl.
 4. A compound in accordance with claim 2 whereinX⁻ is Br⁻ or CH₃SO₃ CH₃ SO ₃ ⁻ .
 5. A compound of the formula

wherein X⁻ is a physiologically acceptable anion.
 6. A compound of theformula

wherein X⁻ is a physiologically acceptable onion.
 7. A compound of theformula


8. A compound of the formula

wherein R₁ is 2-thienyl and A is 3α-(6,7-dehydro)-tropanyl methobromide.9. A compound of the formula

wherein R₁ is 2-thienyl and A is 3β-tropanyl methobromide.
 10. Acompound of the formula

wherein R₁ is cyclopentyl and A is 3α-(N-isopropyl)-nortropanylmethobromide.
 11. A method for treating chronic obstructive bronchitiswhich comprises administering, by inhalation, to a subject sufferingfrom the same, a therapeutic amount of a compound in accordance withclaims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
 12. A method for treating slightto moderately severe asthma which comprises administering, byinhalation, to a subject suffering from the same, a therapeutic amountof a compound in accordance with claims 1, 2, 3, 4, 6, 7, 8, 9,
 10. 13.A method for treating vagally induced sinus bradycardia which comprisesadministering, by the intravenous or oral routes, to a subject sufferingfrom the same, a therapeutic amount of a compound in accordance withclaims 1, 2, 3, 4, 6, 7, or 8, 9, 10 .
 14. A pharmaceutical composition,for administration by inhalation, suitable for the treatment of chronicobstructive bronchitis or slight to moderately severe asthma , whichcomprises a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8,9, 10 .
 15. A pharmaceutical composition for oral administration,suitable for the treatment of vagally induced sinus bradycardia, whichcomprises a compound in accordance with claims 1, 2, 3, 4, 6, 7, or 8,9, 10 .
 16. A pharmaceutical composition, for intravenousadministration, suitable for the treatment of vagally induced sinusbradycardia, which comprises a compound in accordance with claims 1, 2,3, 4, 6, 7, or 8, 9, 10 .
 17. A method for treating chronic obstructivebronchitis which comprises administering, by inhalation, to a subjectsuffering from the same, a therapeutic amount of a compound inaccordance with claim
 5. 18. A pharmaceutical composition, foradministration by inhalation, suitable for the treatment of chronicobstructive bronchitis, which comprises a compound in accordance withclaim
 5. 19. A pharmaceutical composition, for administration byinhalation, suitable for the treatment of chronic obstructivebronchitis, comprising an inhalation powder comprising a compound inaccordance with claim 5.